Infections in which bacteria are either slow-growing, dormant or in a biofilm pose a serious clinical challenge for therapy because cells in these states exhibit tolerance to the activity of most antimicrobial agents (12). Osteomyelitis, infective endocarditis, chronic wounds and infections related to indwelling devices are examples of infections that harbor tolerant cells (7, 13). Because most antimicrobial agents exert maximal activity against rapidly dividing cells, antimicrobial therapies for these infections are not optimal, requiring protracted treatment times and demonstrating higher failure rates.
A model theory has been proposed to explain biofilm recalcitrance to chemotherapy (24): the diversity of the growth phases of the biofilm community and the composition of the slime matrix act to limit the effectiveness of otherwise useful antimicrobial agents. It is believed that a population of slow-growing, stationary-phase or ‘persister’ cells within the biofilm can tolerate the killing action of antibacterial agents. This has been demonstrated with the fluoroquinolone antibiotic ofloxacin in which a small population of cells within a biofilm were not killed by this agent (41). Furthermore, it is thought these tolerant cells are protected from immune clearance in vivo by the biofilm slime matrix and ultimately give rise to relapse infections by reseeding the biofilm once drug levels drop below their antibacterial concentration (24).
Oritavancin is a semi-synthetic lipoglycopeptide in clinical development against serious gram-positive infections. It exerts activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). The rapidity of its bactericidal activity against exponentially-growing S. aureus (≥3-log reduction within 15 minutes to 2 hours against MSSA, MRSA, and VRSA) is one feature that distinguishes it from the prototypic glycopeptide vancomycin (29). Recent work demonstrated that oritavancin has multiple mechanisms of action that can contribute to cell death of exponentially-growing S. aureus, including inhibition of cell wall synthesis by both substrate-dependent and -independent mechanisms (2, 4, 45), disruption of membrane potential and increasing membrane permeability (30), and inhibition of RNA synthesis (4). The ability of oritavancin but not vancomycin to interact with the cell membrane, leading to loss of membrane integrity and collapse of transmembrane potential, correlates with the rapidity of oritavancin bactericidal activity (30). Mechanisms of action beyond substrate-dependent cell wall synthesis inhibition have not been described to date for vancomycin; consequently, vancomycin typically requires 24 h and actively dividing cells to exert bactericidal activity (Belley ICAAC 2006 stat phase poster; Belley 2007 ICAAC stat phase poster; (29)).
There is a need for new methods of treatment for bacteria in slow-growing, stationary-phase and biofilm states.